3-Substituted-4-aryl isoquinolines

ABSTRACT

3-Substituted-4-aryl isoquinolines, e.g. 3-tertiary butyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline, prepared from corresponding isoquinoline intermediates, are useful as anti-diabetic agents.

This is a division of application Ser. No. 411,074 filed Oct. 30, 1973,now U.S. Pat. No. 3,872,125, which is a continuation-in-part ofapplication Ser. No. 339,616, filed Mar. 3, 1973, now abandoned which inturn is a continuation-in-part of application Ser. No. 259,860, filedJune 5, 1972, now abandoned.

This invention pertains to 3-substituted-4-aryl isoquinolines. Moreparticularly, it concerns 3-substituted-4-phenyl orsubstituted-phenyl-1,2,3,4-tetrahydroisoquinolines, intermediates andacid addition salts thereof, and processes for their preparation.

The tetrahydroisoquinolines of this invention may be represented by thefollowing structural formula: ##SPC1##

Where

R₁ represents ##STR1## where R₂ and R₃ are each independently methyl orethyl, or R₂ and R₃ together represent (CH₂)_(n)

Where

n represents 4, 5, or 6, and

R₄, r₅, r₆ and R₇ each independently represent hydrogen, halo of atomicweight 19-36, trifluoromethyl, lower alkyl, i.e. alkyl of 1-4 carbonatoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, and the like, andlower alkoxy, i.e. alkoxy having 1-4 carbon atoms, such as methoxy,ethoxy, isopropoxy, and the like,

Provided that R₆ and R₇ may not represent alkyl at the 8-position, andprovided further that two trifluoromethyl groups or two tert.butylgroups or a trifluoromethyl and a tertiary butyl group are not onadjacent carbon atoms.

The compounds of formula (I) are prepared by hydrogenation ofcorresponding isoquinoline intermediates of formula (II) according tothe following reaction scheme: ##SPC2##

Where

R₁ through R₇ and the provisos are as set out above.

Compounds (II) may be converted into compounds (I) by hydrogenating theformer with a platinum metal catalyst, such as platinum oxide in inertsolvent, such as loweralkanoic acid, e.g. acetic acid, at a temperatureof from about 20°-60° C., preferably about 25°-35° C., at 25-100 psiuntil about two equivalents of hydrogen are absorbed. Neither timetemperature of reaction, pressure nor the solvent used is critical.

The compounds of formula (II) represent an additional aspect of thisinvention and they may be prepared according to the following reactionscheme: ##SPC3##

Where

R₁ through R₇ and the provisos are as set out above, and

X represents halo of atomic weight about 35-80.

Compounds (II) may be prepared from compounds (III) by hydrogenating thelatter at 25-100 p.s.i. in inert alcohol solvent, e.g. lower alkanolssuch as ethanol or isopropanol in the presence of platinum metalcatalyst such as palladium, conveniently palladium on carbon, until oneequivalent of hydrogen is absorbed. The hydrogenation may be performedat a temperature of about 20°-60° C., preferably about 25°-35° C. A basesuch as an alkali metal hydroxide, e.g. sodium hydroxide or potassiumhydroxide, is desirably added to neutralize the HCl liberated in thereaction. Neither the time, temperature, pressure nor solvent utilizedis critical in obtaining compounds (II).

The novel compounds of formula (III) may be obtained according to thefollowing reaction scheme: ##SPC4##

where

X, r₁ through R₇ and the provisos are as set out above.

Compounds (III) are accordingly obtained by treating a compound offormula (IV) with halogenating agent such as PCl₅, POCl₃, SOCl₂, PBr₅,PBr₃ and SOBr₂ and the like optionally in solvent such as aromatichydrocarbon solvent, e.g. benzene or toluene, for about 30-90 minutes ata temperature of about 80°-150° C., conveniently at the refluxtemperature of the system. Neither time, temperature nor solvent arecritical.

The compounds (IV) are also novel and may be prepared according to thefollowing reaction scheme: ##SPC5##

where

R₁ through R₇ and respecting compounds (IV) the provisos are as set outabove, and provided further that R₆ and R₇ may not represent alkyl at aposition ortho to the carbon bonded to the amido group on compounds (V),provided further that two trifluoromethyl groups or two tert.butylgroups or a trifluoromethyl and a tertiary butyl group are not onadjacent carbon atoms.

Compounds (IV) are thus prepared from compounds (V) by treating thelatter with polyphosphoric acid at a temperature of about 70°-120° C.,preferably about 80°-100° C., for about 1/2 to 3 hours. The reactiontime and temperature are not critical.

As will be appreciated by persons skilled in the art, compounds (IV) and(V) may also exist in tautomeric form and the exact form of thecompounds and the amount of compound in each tautomeric form will dependupon such factors as pH, temperature, solvent, etc. For simplicity,compounds (IV) and (V) will be depicted by use of the structures shown,but it will be understood that the corresponding tautomeric forms andtheir use and production are also contemplated by the invention.

The compounds of formula (V) may be obtained according to the followingreaction scheme from compounds (VI) and compounds (VII). ##SPC6##

where

R₁ through R₇ and the provisos are as set out above regarding compounds(V), and

Y represents halo of atomic weight 35-80.

Compounds (VI) and (VII) are first reacted in inert solvent such ashydrocarbon solvents, e.g. benzene or toluene, or ethers such as ethylether or tetrahydrofuran, at a temperature of from about -60° to about10° C. The preferred temperature range is about -20° to -50° C. and thereaction may be run for 1-10 hours. The resulting product is thenhydrolyzed by conventional techniques to provide compounds (V).

The compounds of formula (VI) may be obtained from the compounds of theformula ##SPC7##

where

R₄, r₅, r₆, r₇ and the provisos are as set out above for compounds (V),

by treatment with a lithiating agent, particularly an alkyl or aryllithium compound; n-butyl lithium is especially preferred. This reactionmay be performed in solvent and for a period of time similar to thatdescribed above in connection with the process for obtaining compounds(V). The temperature of the reaction is preferably from about -10° to+10° C. Compound (VI) is normally not isolated from the reaction mixtureand may be used directly in the process for preparing compounds (V)above.

The compounds (VIII) are preparable from compounds of the formula##SPC8##

where

R₄ through R₇ are as set out above,

provided that R₆ and R₇ may not represent alkyl at a position ortho tothe carbon bonded to the acid group, and provided further that twotrifluoromethyl groups or two tertiary butyl groups or a trifluoromethyland a tertiary butyl group are not on adjacent carbon atoms, in astandard manner by halogenating compounds (IX) with halogenating agentssuch as thionyl chloride, and aminating the resulting acid halide withtert.butylamine.

The compounds (IX) are prepared according to the following reactionscheme: ##SPC9##

where

R₄ through R₇ and the provisos for compounds (IX) are as set out above,

provided that R₆ and R₇ on compounds (X) may not represent alkyl at the7-position, and provided further that two trifluoromethyl groups or twotertiary butyl groups or a trifluoromethyl and a tertiary butyl groupare not on adjacent carbon atoms.

Compounds (IX) are prepared from compounds (X) by hydrogenating theformer with hydrogen gas in the presence of a platinum metal catalyst,preferably palladium on carbon. The hydrogenation is convenientlyperformed in alcoholic solvents at room temperature.

Compounds (X) may be prepared according to the following reactionscheme: ##SPC10##

where

R_(o) represents lower alkyl, as defined above, or phenyl, and

R₄ through R₇ are as set out above, as are the provisos respectingcompounds (X), and provided that regarding compounds (XI) R₆ and R₇ donot represent alkyl at a position ortho to the carbon bonded to theamido group, and provided further that two trifluoromethyl groups or twotertiary butyl groups or a trifluoromethyl and a tertiary butyl groupare not on adjacent carbon atoms.

According to the above process, compound (XI) is heated in inerthydrocarbon or halogenated hydrocarbon solvent, e.g. benzene, toluene,pentane, o-dichlorobenzene and the like. The reaction may be carried outat a temperature of about 80°-200° C., and conveniently at the refluxtemperature of the solvent utilized.

The compounds of formula (XI) are obtainable from compounds (XII)according to the following reaction scheme: ##SPC11##

where

R₄ through R₇, R_(o) and the provisos are as set out above for compounds(XI).

Compounds (XI) are prepared from compounds (XII) in inert hydrocarbon orether solvent, e.g. benzene, toluene, ethyl ether, tetrahydrofuran andthe like. The reaction is a two step reaction involving lithiation ofthe compound (XII) to obtain a dilithio intermediate thereof, which inturn is treated with an appropriately substituted benzaldehyde (XIII) toobtain compounds (XI). The lithiation is preferably performed at atemperature between about -60° to +10° C. for about 1-3 hours whereasthe second step, generally performed without separation of the dilithiointermediate, is performed between -10° and +10° C. for about 1-3 hours.

Unless specifically indicated otherwise, the products of each of thereactions described above may be recovered by conventional techniquessuch as crystallization, filtration, trituration, and the like.

Certain of the compounds of formulae (VII), (XII) and (XIII) are knownand may be prepared according to methods disclosed according to theliterature. The compounds of formulae (VII), (XII) and (XIII) notspecifically disclosed may be prepared by methods analogous to those inthe literature from known compounds.

Compounds (I) and (II) may exist in the form of their acid additionsalts. Said salts and their respective free bases may be converted fromone to the other by conventional techniques and are chemicallyinterchangeable for purposes of the above described process. Thecompounds of formula (I) exist in racemic form or in the form ofoptically active isomers. The separation and recovery of the respectiveisomers may be readily accomplished employing conventional techniques,and such isomers are included within the scope of the invention.

The compounds of formula (I) above are useful because they possesspharmacological properties in animals, such as mammals. In particular,the compounds may be used as anti-diabetic agents as indicated by theiractivity in rats orally administered active agent at a dose of 200 mg/kgof animal body weight. The rats are made diabetic by intraperitonealinjection of 250 mg/kg of alloxan monohydrate four days prior to theexperiment. Only those rats showing positive reactions for sugar inurine are used. The positive reactions are as shown on "Clinistix" madeby Ames Company, Division of Miles Laboratories, Inc., Elkhart, Ind. anddescribed in U.S. Pat. Nos. 3,453,180; 3,164,534; 3,123,443; 3,050,373and 2,981,606.

Two hours after oral administration of the drug, the rats areanesthetized by intraperitoneal injection of sodium hexobarbital (120mg/kg). Blood is taken by incision of the jugular vein and is collectedin a test tube which contains 0.1 ml. of heparin (1,000 units/ml). Theheparinized blood is used to determine blood sugar level.

Anti-diabetic activity is determined by comparison of the mean bloodsugar (mg %) of drug treated rats with that of controls (given vehicletwo hours before sacrificing).

For such usage, the compounds of formula (I) may be combined with apharmaceutically acceptable carrier or adjuvant, and may be administeredorally in such forms as tablets, capsules, elixers, suspensions and thelike, or parenterally in the form of an injectable solution orsuspension. The dosage will vary depending upon the mode ofadministration utilized and the particular compound employed.

As indicated above, the compounds of formula (I) may be similarlyadministered in the form of their non-toxic pharmaceutically acceptableacid addition salts. Such salts possess the same order of activity asthe free base, are readily prepared by reacting the base with anappropriate acid and accordingly are included within the scope of theinvention. Representative of such salts are the mineral salts, such ashydrochloride, hydrobromide, sulfate, phosphate and the like and theorganic acid salts, such as the succinate, benzoate, acetate,p-toluenesulfonate, benzenesulfonate and the like.

As noted above, the compounds of formula (I) exist as optical isomers.In some cases, greater pharmacological activity or other beneficialattribute may be found for a particular isomer and in such instancesadministration of such isomer may be employed.

In general, satisfactory results are obtained when the compounds (I) areadministered at a daily dosage of from about 4-400 mg/kg of animal bodyweight, preferably orally and in divided doses, 2 to 4 times a day or insustained release form. For most larger mammals (e.g. primates) thetotal daily dosage is from about 250-2000 mg. per day. Dosage formssuitable for internal use comprises from about 60 mg. to about 1000 mg.of the active compound in intimate admixture with a solid or liquidpharmaceutically acceptable carrier or diluent.

Tablets containing 100 mg. of active ingredient and 250 mg. of lactosemay be prepared by conventional techniques and are useful in treatingdiabetes at a dose of one tablet 2 to 4 times a day.

EXAMPLE 1 N-tert.butyl-α-phenyl-o-toluamide

To a flask equipped with a stirrer, dropping funnel, condenser and gasinlet tube maintained under a nitrogen atmosphere there is added at roomtemperature 67.5 g. (0.5 mole) N-methyl benzamide and 1200 ml. drytetrahydrofuran. The reaction flask is immersed in an ice bath andcooled to an internal temperature of 5° C. Stirring is initiated and 688ml. of 1.6 M. n-butyl lithium (1.1 mole) in hexane is added dropwiseover about 1 hour maintaining temperature below 8° C. The resultingdilithio salt is stirred at 5° C. for an additional hour and then asolution of 58.5 g. (0.55 mole) of benzaldehyde in 500 ml.tetrahydrofuran is added dropwise in about 1 hour maintaining thetemperature between -10° to +10° C. The resulting mixture is stirred at5° C. for 1 hour longer and 300 ml. of saturated ammonium chloride isadded maintaining the temperature at about 10° C. The layers areseparated and the organic phase dried over anhydrous magnesium sulfate,filtered and evaporated in vacuo to giveα-hydroxy-N-methyl-α-phenyl-o-toluamide.

A mixture of 76.5 g. of α-hydroxy-N-methyl-α-phenyl-o-toluamide and(0.314 mole) 150 ml. o-dichlorobenzene is heated at reflux for 18 hours.The mixture is cooled and filtered and the resulting solid trituratedwith cold ether to give 3-phenyl phthalide.

When the above process is carried out and in place of benzaldehyde thereis used

a. p-chlorobenzaledhyde,

b. o-tolualdehyde,

c. p-methoxybenzaldehyde,

d. m-trifluoromethylbenzaldehyde,

e. 3,4-dichlorobenzaldehyde, or

f. p-tolualdehyde

there is obtained through the corresponding intermediateα-hydroxy-N-methyl-o-toluamide,

a. 3-p-chlorophenyl phthalide,

b. 3-o-tolyl phthalide,

c. 3-p-methoxyphenyl phthalide,

d. 3-m-trifluoromethylphenyl phthalide,

e. 3-(3,4-dichlorophenyl) phthalide, or

f. 3-p-tolyl phthalide, respectively.

When the above detailed procedure is carried out and in place ofN-methyl benzamide there is used l

g. o-chloro-N-phenyl benzamide,

h. N-methyl-p-toluamide,

i. N-methyl-m-trifluoromethyl benzamide, or

j. p-methoxy-N-methyl benzamide,

there is obtained through the corresponding intermediateα-hydroxy-α-phenyl-o-toluamide,

g. 7-chloro-3-phenyl phthalide,

h. 5-methyl-3-phenyl phthalide,

i. 6-trifluoromethyl-3-phenyl phthalide, or

j. 5-methoxy-3-phenyl phthalide, respectively.

A mixture of 55.2 g. of 3-phenyl phthalide (0.263 mole), 600 ml. ethanoland 5.9 g. of 10% Pd/C is hydrogenated at room temperature and 50 psiuntil 1 equivalent of H₂ is absorbed. The catalyst is removed byfiltration and the solvent removed in vacuo and the residue trituratedin petroleum ether to give α-phenyl-o-toluic acid; m.p. 101°-104° C.

To a mixture of 49.8 g. (0.235 mole) α-phenyl-o-toluic acid, 300 ml.ether and 10 ml. pyridine, add dropwise with stirring 25 ml. (0.35 mole)of thionyl chloride. The resulting mixture is stirred 21 hours at roomtemperature then filtered and the solvent removed in vacuo. Theresulting acid chloride is dissolved in 150 ml. ether and added dropwiseto 35.7 g (0.48 mole) of tert.butylamine in 500 ml. of ethyl ether, andthe mixture cooled to 0° C. After addition is complete the resultingmixture is stirred 1 hour at room temperature, the layers separated, theether washed with 100 ml. of water, 100 ml. of 2N sodium hydroxide andthen with water again, dried over magnesium sulfate, filtered andevaporated to give N-tert.butyl-α-phenyl-o-toluamide; m.p. 91°- 92° C.

When the procedure described in the above two paragraphs is carried outand in place of 3-phenyl phthalide there is used

a. 3-p-chlorophenyl phthalide,

b. 3-o-tolyl phthalide,

c. 3-p-methoxyphenyl phthalide,

d. 3-m-trifluoromethylphenyl phthalide,

e. 3-(3,4-dichlorophenyl) phthalide,

f. 3-p-tolyl phthalide,

g. 7-chloro-3-phenyl phthalide,

h. 5-methyl-3-phenyl phthalide,

i. 6-trifluoromethyl-3-phenyl phthalide, or

j. 5-methoxy-3-phenyl phthalide,

there is obtained through the corresponding acid and acid halide,

a. α-(p-chlorophenyl)-N-tert.butyl-o-toluamide,

b. N-tert.butyl-α-(o-tolyl)-o-toluamide,

c. α-(p-methoxyphenyl)-N-tert.butyl-o-toluamide,

d. N-tert.butyl-α-(m-trifluoromethylphenyl)-o-toluamide,

e. α-(3,4-dichlorophenyl)-N-tert.butyl-o-toluamide,

f. N-tert.butyl-α-(p-tolyl)-o-toluamide,

g. 6-chloro-N-tert.butyl-α-phenyl-o-toluamide,

h. N-tert.butyl-4-methyl-α-phenyl-o-toluamide,

i. N-tert.butyl-α-phenyl-5-trifluoromethyl-o-toluamide, or

j. 4-methoxy-N-tert.butyl-α-phenyl-o-toluamide, respectively.

EXAMPLE 2 N-tert.butyl-α-phenyl-α-pivaloyl-o-toluamide

To a flask equipped with a stirrer, dropping funnel, condenser and gasinlet tube and maintained under a nitrogen atmosphere there is added atroom temperature 59 g. (0.221 mole) of N-tert.butyl-α-phenyl-o-toluamidein 1000 ml. dry tetrahydrofuran. The flask is immersed in an ice bathand cooled to an internal temperature of 5° C. Stirring is initiated and336.5 ml. (0.490 mole) of n-butyl lithium (15% in hexane) is addeddropwise in about 1 hour maintaining the temperature below 8° C. Theresulting solution is stirred 2 hours at room temperature, cooled to 5°C., and 26.6 g. (0.221 mole) of pivaloyl chloride in 250 ml. of drytetrahydrofuran is added dropwise maintaining temperature below 8° C.After addition, the mixture is stirred 2 hours at room temperature andhydrolyzed with 150 ml. of saturated ammonium chloride, the resultingsolution is filtered and the layers separated. The organic layer isdried over magnesium sulfate, filtered and evaporated in vacuo. Theresidue is triturated with ether to giveN-tert.butyl-α-phenyl-α-pivaloyl-o-toluamide; m.p. 157°-161° C.

When the above process is carried out and in place ofN-tert.butyl-α-phenyl-o-toluamide there is used

a. α-(p-chlorophenyl)-N-tert.butyl-o-toluamide,

b. N-tert.butyl-α-(o-tolyl)-o-toluamide,

c. α-(p-methoxyphenyl)-N-tert.butyl-o-toluamide,

d. N-tert.butyl-α-(m-trifluoromethylphenyl)-o-toluamide,

e. α-(3,4-dichlorophenyl)-N-tert.butyl-o-toluamide,

f. N-tert.butyl-α-(p-tolyl)-o-toluamide,

g. 6-chloro-N-tert.butyl-α-phenyl-o-toluamide,

h. N-tert.butyl-4-methyl-α-phenyl-o-toluamide,

i. N-tert.butyl-α-phenyl-5-trifluoromethyl-o-toluamide, or

j. 4-methoxy-N-tert.butyl-α-phenyl-o-toluamide,

there is obtained

a. α-(p-chlorophenyl)-N-tert.butyl-α-pivaloyl-o-toluamide,

b. N-tert.butyl-α-pivaloyl-α-(o-tolyl)-o-toluamide,

c. α-(p-methoxyphenyl)-α-pivaloyl-N-tert.butyl-o-toluamide,

d. N-tert.butyl-α-pivaloyl-α-(m-trifluoromethylphenyl)-o-toluamide,

e. α-(3,4-dichlorophenyl)-N-tert.butyl-α-pivaloyl-o-toluamide,

f. N-tert.butyl-α-pivaloyl-α-(p-tolyl)-o-toluamide,

g. 6-chloro-N-tert.butyl-α-pivaloyl-α-phenyl-o-toluamide,

h. N-tert.butyl-4-methyl-α-pivaloyl-α -phenyl-o-toluamide, l

i. N-tert.butyl-α-pivaloyl-α-phenyl-5-trifluoromethyl-o-toluamide, or

j. 4-methoxy-N-tert.butyl-α-pivaloyl-α-phenyl-o-toluamide, respectively.

When the above process is carried out and in place of pivaloyl chloridethere is used 2,2-dimethylbutanol chloride or 1-methylcyclohexanecarbonylbromide, there is obtained

k. α-(2,2-dimethylbutanoyl)-N-tert.butyl-α-phenyl-o-toluamide, or

l. N-tert.butyl-α-(1-methyl cyclohexanoyl)-α-phenyl-o-toluamide,respectively.

EXAMPLE 3 3-tert.butyl-4-phenyl isocarbostyril

In portions 79 g. (0.225 mole) ofN-tert.butyl-α-phenyl-α-pivaloyl-o-toluamide is added to 1130 mg. ofpolyphosphoric acid heated to 90° C. The mixture is stirred 11/2 hoursat 90° C. and poured onto ice with stirring. The resulting solid isfiltered and washed thoroughly with water. The solid is recrystallizedfrom chloroform: ethyl ether (1:1) to give3-tert.butyl-4-phenyl-isocarbostyril; m.p. 284°- 286° C.

when the above process is carried out and in place ofN-tert.butyl-α-phenyl-α-pivaloyl-o-toluamide there is used

a. α-(p-chlorophenyl)-N-tert.butyl-α-pivaloyl-o-toluamide,

b. N-tert.butyl-α-pivaloyl-α-(o-tolyl)-o-toluamide,

c. α-(p-methoxyphenyl)-α-pivaloyl-N-tert.butyl-o-toluamide,

d. N-tert.butyl-α-pivaloyl-α-(m-trifluoromethylphenyl)-o-toluamide,

e. α-(3,4-dichlorophenyl)-N-tert.butyl-α-pivaloyl-o-toluamide,

f. N-tert.butyl-α-pivaloyl-α-(p-tolyl)-o-toluamide,

g. 6-chloro-N-tert.butyl-α-pivaloyl-α-phenyl-o-toluamide,

h. N-tert.butyl-4-methyl-α-pivaloyl-α-phenyl-o-toluamide,

i. N-tert.butyl-α-pivaloyl-α-phenyl-5-trifluoromethyl-o-toluamide, or

j. 4-methoxy-N-tert.butyl-α-pivaloyl-α-phenyl-o-toluamide,

k. α-(2,2-dimethylbutanoyl)-N-tert.butyl-α-phenyl-o-toluamide, or

l. N-tert.butyl-α-(1-methyl cyclohexanoyl)-α-phenyl-o-toluamide,

there is obtained

a. 3-tert.butyl-4-(p-chlorophenyl) isocarbostril,

b. 3-tert.butyl-4-(o-tolyl) isocarbostyril,

c. 3-tert.butyl-4p-methoxyphenyl) isocarbostril,

d. 3-tert.butyl-4-(m-trifluoromethylphenyl) isocarbostyril,

e. 3-tert.butyl-4-(3,4-dichlorophenyl) isocarbostyril,

f. 3-tert.butyl-4-(p-tolyl) isocarbostyril,

g. 3-tert.butyl-8-chloro-4-phenyl isocarbostyril,

h. 3-tert.butyl-6-methyl-4-phenyl isocarbostyril,

i. 3-tert.butyl-4-phenyl-7-trifluoromethyl isocarbostyril,

j. 3-tert.butyl-6-methoxy-4-phenyl isocarbostyril

k. 3-(2,2-dimethylbutyl)-4-phenyl isocarbostyril, or

l. 3-1(1-methyl cyclohexyl)-4-phenyl isocarbostyril, respectively.

EXAMPLE 4 3-tert.butyl-1-chloro-4-phenyl isoquinoline

A mixture of 11 g. (0.04 mole) of 3-tert.butyl- 4-phenyl isocarbostyriland 40 ml. of phosphorous oxychloride is refluxed for one hour. Theexcess solvent is removed in vacuo and ice is added to the residue andstirred. The resulting solid is filtered and washed with water andrecrystallized from ethanol to give 3-tert.butyl-1-chloro-4-phenylisoquinoline; m.p. 139°-140° C.

When the above process is carried out and in place of phosphorousoxychloride there is used phosphorous pentachloride or thionyl chloride,the identical product is again obtained.

When the above process is carried out and in place of 3-tert.butyl-4-phenyl isocarbostyril there is used

a. 3-tert.butyl-4-(p-chlorophenyl) isocarbostril,

b. 3-tert.butyl-4-(o-tolyl) isocarbostyril,

c. 3-tert.butyl-4(p-methoxyphenyl) isocarbostril,

d. 3-tert.butyl-4-(m-trifluoromethylphenyl) isocarbostyril,

e. 3-tert.butyl-4-(3,4-dichlorophenyl) isocarbostyrll,

f. 3-tert.butyl-4-(p-tolyl) isocarbostyril,

g. 3-tert.butyl-8-chloro-4-phenyl isocarbostyril,

h. 3-tert.butyl-6-methyl-4-phenyl isocarbostyril,

i. 3-tert.butyl-4-phenyl-7-trifluoromethyl isocarbostyril,

j. 3-tert.butyl-6-methoxy-4-phenyl isocarbostyril

k. 3-(2,2-dimethylbutyl)-4-phenyl isocarbostyril, or

l. 3-1(1-methyl cyclohexyl)-4-phenyl isocarbostyril,

there is obtained

a. 3-tert.butyl-1-chloro-4-(p-chlorophenyl) isoquinoline,

b. 3-tert.butyl-1-chloro-4-(o-tolyl) isoquinoline,

c. 3-tert.butyl-1-chloro-4-(p-methoxyphenyl) isoquinoline,

d. 3-tert.butyl-1-chloro-4(m-trifluoromethylphenyl) isoquinoline,

e. 3-tert.butyl-1-chloro-4-(3,4-dichlorophenyl) isoquinoline,

f. 3-tert.butyl-1-chloro-4-(p-tolyl) isoquinoline,

g. 3-tert.butyl-1,8-dichloro-4-phenyl isoquinoline,

h. 3-tert.butyl-1-chloro-6-methyl-4-phenyl isoquinoline,

i. 3-tert.butyl-1-chloro-4-phenyl-7-trifluoromethyl isoquinoline,

j. 3-tert.butyl-1-chloro-6-methoxy-4-phenyl isoquinoline,

k. 3-(2,2-dimethylbutyl)-1-chloro-4-phenyl isoquinoline, or

l. 3-(1-methylcyclohexyl)-1-chloro-4-phenyl isoquinoline, respectively.

EXAMPLE 5 3-tert.butyl-4-phenyl isoquinoline hydrochloride

A mixture of 21.7 g. (0.073 mole) of 3-tert.butyl-1-chloro-4-phenylisoquinoline, 4.09 g. (0.073 mole) potassium hydroxide, 1.09g 10%palladium on carbon and 1 liter of ethanol is hydrogenated at roomtemperature and 50 psi until 1 equivalent of hydrogen is absorbed. Thecatalyst is filtered off and washed with ethanol, combined ethanolportions are evaporated in vacuo. The residue is dissolved in ethylether, washed with water, dried, and filtered and the filtrate treatedwith gaseous HCl. The resulting white solid is filtered andrecrystallized from ethanolethyl ether, washed with water, dried, andfiltered and the filtrate treated with gaseous HCl. The resulting whitesolid is filtered and recrystallized from ethanol-ethyl ether (1:1) togive 3-tert.butyl-4-phenyl isoquinoline hydrochloride; m.p. 236°-238° C.

When the above process is carried out and in place of 3-tert.butyl-1-chloro-4-phenyl isoquinoline there is used

a. 3-tert.butyl-1-chloro-4-(p-chlorophenyl) isoquinoline,

b. 3-tert.butyl-1-chloro-4-(o-tolyl) isoquinoline,

c. 3-tert.butyl-1-chloro-4-(p-methoxyphenyl) isoquinoline,

d. 3-tert.butyl-1-chloro-4(m-trifluoromethylphenyl) isoquinoline,

e. 3-tert.butyl-1-chloro-4-(3,4-dichlorophenyl) isoquinoline,

f. 3-tert.butyl-1-chloro-4-(p-tolyl) isoquinoline,

g. 3-tert.butyl-1,8-dichloro-4-phenyl isoquinoline,

h. 3-tert.butyl-1-chloro-6-methyl-4-phenyl isoquinoline,

i. 3-tert.butyl-1-chloro-4-phenyl-7-trifluoromethyl isoquinoline,

j. 3-tert.butyl-1-chloro-6-methoxy-4-phenyl isoquinoline,

k. 3-(2,2-dimethylbutyl)-1-chloro-4-phenyl isoquinoline, or

l. 3-(1-methylcyclohexyl)-1-chloro-4-phenyl isoquinoline,

there is obtained as the hydrochloride

a. 3-tert.butyl-4-(p-chlorophenyl) isoquinoline,

b. 3-tert.butyl-4-(o-tolyl) isoquinoline,

c. 3-tert.butyl-4-(p-methoxyphenyl) isoquinoline,

d. 3-tert.butyl-4-(m-trifluoromethylphenyl) isoquinoline,

e. 3-tert.butyl-4-(3,4-dichlorophenyl) isoquinoline,

f. 3-tert.butyl-4-(p-tolyl) isoquinoline,

g. 3-tert.butyl-8-chloro-4-phenyl isoquinoline,

h. 3-tert.butyl-6-methyl-4-phenyl isoquinoline,

i. 3-tert.butyl-4-phenyl-7-trifluoromethyl isoquinoline,

j. 3-tert.butyl-6-methoxy-4-phenyl isoquinoline,

k. 3-(2,2-dimethylbutyl)-4-phenyl isoquinoline, or

l. 3-(1-methylcyclohexyl)-4-phenyl isoquinoline, respectively.

EXAMPLE 6 3-tert.butyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline

A mixture of 28.5 g. (0.11 mole) of 3-tert.butyl-4-phenyl isoquinoline,2.85 g. platinum oxide and 300 ml. of acetic acid is hydrogenated atroom temperature and 50 psi until two equivalents of hydrogen areabsorbed. The catalyst is filtered off and the acetic acid is evaporatedin vacuo. The residue is dissolved in ether, washed with 50% sodiumhydroxide, water and saturated sodium chloride solution, dried overmagnesium sulfate, filtered and evaporated. The residue is crystallizedfrom petroleum ether to give3-tert.butyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline; m.p. 79°-81° C.

When the above process is carried out and in place of 3-tert.butyl-4-phenyl isoquinoline there is used

a. 3-tert.butyl-4-(p-chlorophenyl) isoquinoline,

b. 3-tert.butyl-4-(o-tolyl) isoquinoline,

c. 3-tert.butyl-4-(p-methoxyphenyl) isoquinoline,

d. 3-tert.butyl-4-(m-trifluoromethylphenyl) isoquinoline,

e. 3-tert.butyl-4-(3,4-dichlorophenyl) isoquinoline,

f. 3-tert.butyl-4-(p-tolyl) isoquinoline,

g. 3-tert.butyl-8-chloro-4-phenyl isoquinoline,

h. 3-tert.butyl-6-methyl-4-phenyl isoquinoline,

i. 3-tert.butyl-4-phenyl-7-trifluoromethyl isoquinoline,

j. 3-tert.butyl-6-methoxy-4-phenyl isoquinoline,

k. 3-(2,2-dimethylbutyl)-4-phenyl isoquinoline, or

l. 3-(1-methylcyclohexyl)-4-phenyl isoquinoline,

there is obtained

a. 3-tert.butyl-4-(p-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline,

b. 3-tert.butyl-4-(o-tolyl)-1,2,3,4-tetrahydroisoquinoline,

c. 3-tert.butyl-4-(p-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline,

d.3-tert.butyl-4-(m-trifluoromethylphenyl)-1,2,3,4-tetrahydroisoquinoline,

e. 3-tert.butyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline,

f. 3-tert.butyl-4-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline,

g. 2-tert.butyl-8-chloro-4-phenyl-1,2,3,4-tetrahydroisoquinoline,

h. 3-tert.butyl-6-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline,

i.3-tert.butyl-4-phenyl-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline,

j. 3-tert.butyl-6-methoxy-4-phenyl-1,2,3,4-tetrahydroisoquinoline,

k. 3-(2,2-dimethylbutyl)-4-phenyl-1,2,3,4-tetrahydroisoquinoline,

or

l. 3-(1-methylcyclohexyl)-4-phenyl-1,2,3,4-tetrahydroisoquinoline,respectively.

The title compound of this example is an effective antidiabetic whenorally administered to diabetic animal at a dosage of 100 mg. twice perday.

What is claimed is:
 1. A compound of the formula ##SPC12##where R₁represents ##EQU1## where R₂ and R₃ are each, independently, methyl orethyl, or R₂ and R₃ together represent (CH₂)_(n) where n represents 4, 5or 6,where R₄, r₅, r₆, r₇ each, independently, represent hydrogen, haloof atomic weight 19-36, trifluoromethyl, lower alkyl having 1-4 carbonatoms, or lower alkoxy having 1-4 carbon atoms, provided that R₆ and R₇may not represent said lower alkyl at the 8-position, and providedfurther that two trifluoromethyl groups or two tertiary butyl groups ora trifluoromethyl group and a tertiary butyl group are not on adjacentcarbon atoms.and X represents halo of atomic weight about 35-80.
 2. Thecompound of claim 1 which is3-tert.butyl-1-chloro-4-phenyl-isoquinoline.